TW200812595A - Solid preparation comprising adenosine-5'-triphosphate or physiologically acceptable salt thereof - Google Patents

Abstract

Disclosed is a solid preparation which comprises adenosine 5'-triphosphate or a physiologically acceptable salt thereof, which has a highly maintained active ingredient content even after being stored for a long period, and which has a moisture activity of 0.28 Aw or lower at 25 DEG C. The solid preparation preferably is in the form of a tablet, more preferably in the form of a film-coated tablet.

Description

200812595 (1) Description of the Invention [Technical Field of the Invention] The present invention relates to a solid preparation containing a stable adenosine 5 / triphosphate or a physiologically acceptable salt thereof. More specifically, it is a solid preparation containing adenosine triphosphate or a physiologically acceptable salt thereof, which is highly retained in the active ingredient content after long-term storage. φ [Prior Art] Adenosine 5 /triphosphate is a compound with a high-energy phosphate bond, which releases a large amount of energy when hydrolyzed to adenosine 5 / diphosphate and phosphoric acid. In organisms, adenosine 5/triphosphate is mainly used as a source of energy for the reaction, and as a phosphate donor, it is involved in metabolic reactions. As for the case where adenosine 5 /triphosphate is used as a pharmaceutical, it is known to be used as a chronic gastrointestinal tract for head trauma sequelae, arrhythmia, regulation of eye fatigue during regulation of eye fatigue, and expression of digestive tract function. Therapeutic agent for inflammation. Further, a composition containing adenosine triphosphate (ATP) which increases the muscle torsion and reduces the effective amount of muscle fatigue is also known (Patent Document ^1). For example, ADETPHOS ingot (Hinghe Co., Ltd.) and ATP enteric ingot "First" (First Pharmaceutical Co., Ltd.) can be mentioned in the form of a solid preparation containing adenosine 5 > triphosphate. Wait. However, since adenosine 5 / triphosphate is unstable to water and easily decomposes, the content of the active ingredient in the preparation is decreased over time due to long-term storage, and a desiccant such as silicone is used for refrigerating in the passage of the passage. However, there is a problem in that the additional storage method is employed, and the cost of the production is increased by the addition of the desiccant -4-200812595 (2), or the handling property is deteriorated due to refrigeration during the circulation. In addition, there may be a user who ingests the silicone as a desiccant. As a method for stabilizing a derivative such as ADP, a method for regulating the moisture content to 4.0% or less is disclosed in Japanese Laid-Open Patent Publication No. SHO-49-87684, but the method is based on the regulation of inclusion in ADP. It is not intended to stabilize the ATP in the solid preparation by the water content in the crystal of the substance to achieve stability (in the same manner as in the first embodiment). Φ Patent Document 1: Special Table 2 0 04 · 5 3 5 4 1 7 pp. Patent Document 2: JP-A-49-84 76 [Invention] The object of the present invention is to provide adenosine 5 / triphosphate Or a solid preparation of a salt which is physiologically acceptable, and a stable solid preparation which maintains an active ingredient content after long-term storage. The inventors of the present invention found that the solid preparation containing adenosine 5 > triphosphate or a physiologically acceptable salt thereof was found to have a water activity at 25t in order to solve the above problem. 〇.28Aw or less, it is possible to provide a stable solid preparation which does not substantially reduce the content of adenosine v 5 /triphosphate or a physiologically acceptable salt thereof in a solid preparation even after long-term storage. The present invention has been completed on the basis of the aforementioned knowledge. That is, the present invention is a solid preparation containing adenosine 5 / triphosphate or a physiologically acceptable salt thereof, and is provided in a solid preparation having a water activity of 25 ° C or less at 25 ° C. According to a preferred mode of the present invention, the aforementioned solid preparation can be provided at -5-

200812595 (3) Adenosine triphosphate or physiologically acceptable salt content is 1 in the form of a tablet relative to the total mass of the solid preparation; The type of the active film ingot. The solid preparation of the present invention is characterized by excellent preservation stability even if it is maintained for a long period of time to maintain adenosine 5 > triphosphate or physiologically acceptable. According to the present invention, it is possible to avoid an increase in the manufacturing cost for the desiccant drying agent, S complicated storage, and no possibility of eating the desiccant. The preparation does not cause swelling due to swelling during long-term storage, and does not cause adhesion between the solid preparations. The expansion after storage in the g period of the present invention results in an excellent effect of storage and transportation of the auxiliary tablet. The adenosine triphosphate or the salt 3 used in the present invention is well known to those skilled in the art and can be easily obtained by related art. The adenosine triphosphate or a physiologically acceptable salt thereof is an alkali metal salt such as a sodium salt or a potassium salt, or a magnesium salt or a barium salt. Among them, adenosine 5 / disodium triphosphate is preferred. In the present invention, "water activity" means a type of all moisture 4 contained in a solid preparation containing gland = § and / or a salt thereof, and can be classified into bound water or free water. The components in the phase-fixed preparation are combined with the combination of temperature and humidity to easily move and evaporate. . The solid preparation of the fixed-temperature sealed container in which the solid preparation is placed, in an amount of ～80% by mass; after adjusting the water by the film coating, the content of the salt is also high, and the solid preparation is in the passage of the present invention. The solid appearance changes, and the type preparation does not produce when the long product is inhibited. There is no particular limitation on the type of the formula. For example, an alkaline earth metal such as a salt: 5/triphosphate is free water (from for strong ground, The free water will be proportional to the parameter steam V, -6 - 200812595 (4) When the pure water vapor pressure is PO, 'P/PO can be used to calculate the water activity. The water activity of the solid preparation at 25 ° C can be easily measured by a known method, and can be measured, for example, using AQUALAB CX-3TE (manufactured by Decagon Co., Ltd.). * The solid preparation of the present invention has a water activity of 0.2 8 Aw or less at 25 ° C, a range of 0.08 Aw to 0.28 Aw, a range of 0_09 Aw to 0.28 Aw, and a range of O. 10 OA to 0.28 AW. good. The solid preparation of the present invention having water φ activity in the above range, the adenosine 5 > triphosphate of the active ingredient or the physiologically acceptable salt content thereof can be highly maintained after long-term storage. It maintains a high level of phase content. The water activity of the solid preparation falls within the above range, and for example, the solid preparation can be dried to a water activity of 0.28 Aw or less at 25 °C. More specifically, a film-forming machine such as a bread type laminator, a ventilating laminator, or a fluidized layer laminator may be used to dry the solid preparation or to perform a coating treatment while adjusting the solid preparation. Moisture or a method in which the solid preparation is placed in a vacuum φ dryer and a box dryer to be dried to adjust to a predetermined water activity. Alternatively, the solid preparation and the silicone resin may be stored and fixed for a predetermined period of time, and then adjusted to a predetermined water activity. Among them, the method of adjusting the water activity is not limited to the specific method described above, and the relevant one can appropriately select it. The form of the solid preparation of the present invention is not particularly limited, and a suitable form can be selected, but it is preferably a solid preparation for oral administration such as a tablet, a granule or a fine granule. The content of the salt of physiologically acceptable adenosine 5 /triphosphate or -7-200812595 (5) in the solid preparation of the present invention is not particularly limited, for example, relative to the total mass of the solid preparation. 1 to 80% by mass is preferred, 1·5 to 75% by mass is more preferable, and 2 to 70% by mass is particularly preferable. The solid preparation of the present invention may contain other pharmaceutically active ingredients in addition to adenosine 5 / triphosphate or a physiologically acceptable salt thereof. The pharmaceutically active ingredient may, for example, be caffeine, vitamins, or crude drugs. These pharmaceutically active ingredients may be separately mixed with the solid preparation of the present invention, and φ may be used in combination of two or more kinds. The caffeines may, for example, be anhydrous caffeine, caffeine, sodium benzoic acid caffeine or the like. Examples of the vitamins include vitamin Β 1, vitamin Β 2, vitamin Β 6, vitamin Β 1, vitamin C, hesperidin and derivatives thereof, and salts of these substances. Examples of the crude drug include garlic, ephedra, Nantianshi, Yingpi, Yuanzhi, licorice, platycodon, psyllium, plantain, lycopene, meiyuanzhi, fritillary, fennel, cork, berberine, medlar, chamomile, cinnamon, Gentian, bezoar, animal bile (including bear bile), satay, ginger, ® atractylodes, clove, tangerine peel, atractylodes, earthworm, bamboo ginseng, ginseng, etc. For the manufacture of the solid preparation of the present invention containing adenosine 5/triphosphate or a physiologically acceptable salt thereof, one or more preparation additives may be used. The type of the additive for the preparation is not particularly limited, and for example, an excipient, a binder, a disintegrator or a slip agent can be used. Examples of the excipients include lactose, starch, crystalline cellulose, sucrose, mannitol, light anhydrous citric acid, and hardened oil. The binder may, for example, be hydroxypropylmethylcellulose, hydroxypropylcellulose, gelatin, gelatinized starch, polyvinylpyrrolidone, polyvinyl alcohol, flulan or the like. Examples of the disintegrant include -8-200812595 (6) carboxymethylcellulose, carboxymethylcellulose calcium, sodium carboxymethylcellulose, croscarmellose sodium, crosslinked iodine, corn starch, low substitution. Hydroxypropyl cellulose and the like. The slip agent may, for example, be magnesium stearate or talc. The solid preparation of the present invention preferably forms a film on the surface. Forming a film "Polyacrylic acid copolymer-L, acrylic copolymer-LD, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose succinate, etc. can be used for the polymer. When the film is formed, a lemon can also be used in combination. a plasticizer such as triethyl acrylate or polyethylene glycol, φ talc, titanium oxide, yellow ferric oxide, ferric oxide, legal pigment, light anhydrous citric acid, aqueous cerium oxide, etc. by mixing These powders can be concealed and shading of the shaped preparation, or can also color the solid preparation. When the solid preparation is a tablet, it can be formed into a sugar-coated or dry-coated ingot after the film is formed. The solid preparation can be produced by a known method, for example, when it contains adenosine 5 / triphosphate or a physiologically acceptable salt thereof, it can be adenosine 5 > triphosphate or physiologically acceptable. In the salt, other active ingredients such as active ingredients and preparations are added, and granulated according to a usual method, and then produced by compression molding using a tableting machine. Further, when a film coat is added to the solid preparation, a coating liquid can be used. Coating the solid preparation A general method such as cloth or spray is used for the film coating. In particular, the spray coating method is simple and preferable. For example, a ventilation type such as a Dora laminator (manufactured by POWREX) and a high-speed laminator (FREUND) is used. In the laminator, a gelatin containing an adenosine triphosphate or a physiologically acceptable salt thereof is applied to prepare a film coat, and at this time, the solid preparation of the present invention can be produced by adjusting a predetermined water activity. When the surface of the solid preparation is required to have a luster, it may be preferably -9 - 200812595 (7) palm wax or the like according to a common method. The solid preparation of the present invention can express adenosine 5 / triphosphate or physiology For the purpose of the expected efficacy of the salt, and for the purpose of prevention and / or treatment for the patient, for example, as a sequela of head trauma ^, arrhythmia, or chronic dysfunction of the digestive tract A drug for the prevention and/or treatment of gastroenteritis, or a drug that can be used as a regulating function for regulating eye fatigue. Further, it can also be used as disclosed in • Patent Application 2005 - 1 5 5 3 1 9 [Embodiment] Hereinafter, the present invention will be specifically described by way of examples, but the present invention is not limited to these examples. Example 1 Φ 600 g of adenosine 5, triphosphate Sodium, 240 g of vitamin B1, 240 g of vitamin B6, 0.6 g of vitamin B12, 240 g of hydroxypropylcellulose, 4034.4 g of crystalline cellulose, 600 g of carboxymethylcellulose, and then added ll〇〇g After ethanol, granulation, drying and granulation were carried out, and 45 g of magnesium stearate was further added to prepare granules for tableting. The tablet was compressed and formed into pellets to obtain 200 mg of a tablet. The ingot is prepared by dissolving and dispersing 2 4 〇〇g of purified water, 410 g of acrylic copolymer-LD, 123 g of talc, 61.6 g of diethyl citrate, and 5.4 g of titanium oxide. A film-coating liquid was prepared by using a ventilating laminating machine (-10-(8) 200812595 Dolly Laminator DRC-650DS Co., Ltd., manufactured by p〇WREX) to prepare a film ingot of 220 mg in one shot. The type of film is adjusted to have a water activity of 〇·28 AW (25 ° C), and the present invention is obtained. Formulations. Further, the water activity at 25 ° C was measured using AQUALABCX-3TE (manufactured by Decagon Co., Ltd.). Example 2 φ The same film ingot as in Example 1 was obtained, and the water-repellent activity was adjusted to 0.24 using a ventilating laminator. Example 3 A film ingot of the same manner as in Example 1 was obtained, and the water-repellent activity was adjusted to 0.19 using a ventilating laminator. Example 4 φ The same film-coated tablet as in Example 1 was obtained, and the water-repellent activity was adjusted to 0 · 15 using a ventilating laminator. Example 5 A film ingot of the same manner as in Example 1 was obtained, and the water-repellent activity was adjusted to 〇·1 1 using a ventilating laminator. Example 6 (Comparative Example) A film ingot of the same manner as in Example 1 was obtained, and water was adjusted using a ventilating laminator -11 - 200812595 (9) The activity was 0.37. Example 7 (Comparative Example) A film ingot of the same manner as in Example 1 was obtained, and the water-repellent activity was adjusted to 0.29 using a ventilating laminator. Test Example 1: Residual rate of adenosine 5 > disodium triphosphate φ Each of the tablets obtained in Examples 1 to 7 was taken in 100 tablets, sealed in a No. 5 size bottle, and stored at 6 (TC for 1 month). The content of the adenosine 5 / disodium triphosphate after storage was measured by HPLC, and the residual ratio from the initial was calculated. Test Example 2: Change in appearance The tablets obtained in Examples 1 to 7 were each taken in 100 ingots and loaded separately. After sealing the No. 5 bottle, store it at 60 ° C for 1 month. Calculate the change rate of appearance. The change rate of appearance is calculated by the following formula: φ Appearance change rate (%) = (60 ° C - thickness of ingot after month - Initial ingot thickness) / initial ingot thickness χ 1 〇〇 (%) Test Example 3: Adhesion degree Each of the tablets obtained in Examples 1 to 7 was taken to 100 ingots, and each was placed in a No. 5 size bottle and sealed at 60 ° C. After 1 month of storage, the degree of adhesion of the tablet was evaluated. The evaluation was based on the following criteria: 2: Adhesion of strength 1: Mild adhesion 0: No adhesion test results 1 to 3 were shown in Table 1. -12 - 200812595 (10) Table 1 Example 1 Case 2 Case 3 Case 4 Case 5 Case 6 Case 7 Water activity (Aw) 0.28 0.24 0.1 9 0.15 0.11 0.37 0.29 Residual rate (%) 7 5 79 90 92 94 1 15 Appearance change rate (%) 0.0 0.0 0.0 0.0 0.0 5.4 2.2 Adhesion degree 0 0 0 0 0 2 1 Compared with the tablets of Example 6 and Example 7 (Comparative Example) having a water activity of 0.37 and 0.29 AW at 25 ° C, respectively. In the case of the tablets 1 to 5 having a water activity of 0·28 Aw or less at 25 ° C, the residual rate of adenosine 5 /triphosphate is remarkably high even after storage at 60 ° C for 1 month, even if it is long The adenosine triphosphate or the physiologically acceptable salt content was also sufficiently maintained after the time storage. In the tablets of Examples 1 to 5, the swelling and adhesion of the tablet were remarkably suppressed. Example 8 600 g gland Disodium glycosyltriphosphate disodium, 240 g of vitamin B1, 240 g of vitamin B6, 15 g of vitamin B2, 0.6 g of vitamin B12, 240 g of hydroxypropylcellulose, 300 g of hardened oil, 3719.4 g of crystalline cellulose, 600 g The carboxymethyl cellulose is mixed, and then added with 00 g of ethanol, granulated, dried and granulated, and then 45 g of magnesium stearate is added to prepare granules for tableting. The tablet is compressed and formed into pellets. And one ingot is 200mg (the prime ingot. -13- 200812595 (11) The ingot is refined by 2400g: -LD, 1 23g of talc, 61.5g of diarrhea titanium, 〇·9g of yellow ferric oxide permeate, using a ventilating laminating machine (Doriya; 'part Co., Ltd. made by POWREX), made ^, with the aforementioned aerated film The solid preparation of the present invention is prepared by adjusting the moisture. φ The solid preparation of the present invention is characterized by long-term adenosine 5-triphosphate or physiologically excellent storage stability. Water, 410.lg of acrylic acid copolymerization - triethyl citrate, 5.4g of oxygen dissolved and dispersed, the film coating film machine DRCN650DS type "one spindle is 220mg of film coat activity of 0.22Aw (25°) After the C) period, it can also maintain the salt content of the salt, with -14-

Claims (1)

200812595 (1) X. Patent application scope 1. A solid preparation which is a solid preparation containing adenosine 5-triphosphate or a physiologically acceptable salt thereof. (The water activity is 0.28 Aw or less. > 2) The solid preparation according to claim 1, wherein the adenosine-5/triphosphate or the physiologically acceptable salt solid preparation thereof contains The amount is from 1 to 80% by mass based on the total mass of the solid preparation. φ 3 · The solid preparation according to claim 1 or 2 of the patent application, the type of the tablet. The solid preparation of the third item is a type of film ingot which adjusts the water activity by a film coat after using a ventilating laminating machine. -15- 200812595 VII. Designated representative figure: (1) The designated representative of the case Pictured: No (2), the representative symbol of the representative figure is a simple description: none 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: -3-